Novel highly selective peroxisome proliferator-activated receptor δ (PPARδ) modulators with pharmacokinetic properties suitable for once-daily oral dosing

Lagu, Bharat; Kluge, Arthur F.; Fredenburg, Ross A.; Tozzo, Effie; Senaiar, Ramesh S.; Jaleel, Mahaboobi; Panigrahi, Sunil K.; Tiwari, Nirbhay Kumar; Krishnamurthy, Narasimha Rao; Takahashi, Taisuke; Patane, Michael A.

doi:10.1016/j.bmcl.2017.10.037

Cited by 10 publications

(16 citation statements)

References 8 publications

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“…The clinical development of PPARβ/δ agonists has been unsuccessful to date, and GW501516 remains a banned metabolic modulator by the World Anti-Doping Agency. Pharmaco-equivalents with better safety profiles, however, are still heavily researched [ 135 , 136 ].…”

Section: Regulation Of Ppars During Physical Exercisementioning

confidence: 99%

An aPPARent Functional Consequence in Skeletal Muscle Physiology via Peroxisome Proliferator-Activated Receptors

Phua

Wong

Liao

et al. 2018

IJMS

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Skeletal muscle comprises 30–40% of the total body mass and plays a central role in energy homeostasis in the body. The deregulation of energy homeostasis is a common underlying characteristic of metabolic syndrome. Over the past decades, peroxisome proliferator-activated receptors (PPARs) have been shown to play critical regulatory roles in skeletal muscle. The three family members of PPAR have overlapping roles that contribute to the myriad of processes in skeletal muscle. This review aims to provide an overview of the functions of different PPAR members in energy homeostasis as well as during skeletal muscle metabolic disorders, with a particular focus on human and relevant mouse model studies.

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Section: Regulation Of Ppars During Physical Exercisementioning

confidence: 99%

An aPPARent Functional Consequence in Skeletal Muscle Physiology via Peroxisome Proliferator-Activated Receptors

Phua

Wong

Liao

et al. 2018

IJMS

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“…Although 2d and 2g showed comparable PPARδ activity and plasma clearance values, imidazole 2g was selected for further optimization based on the superior solubility properties (data not shown). Our previous work in the benzamide series (like compound 1 ) demonstrated that modifications of the hexanoic acid side chain significantly influence the observed pharmacokinetic (PK) properties. , Therefore, similar chemistry exploration was undertaken in the imidazole series (e.g., 2g ). Compounds 13–22 were synthesized as shown in Scheme .…”

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confidence: 68%

“…We recently disclosed the potent and selective PPARδ modulator 1 (Figure ), which displayed significantly improved pharmacokinetic properties relative to previously reported compounds. − The X-ray structure of 1 bound to the ligand binding domain (LBD) of the PPARδ receptor revealed that the carbonyl oxygen and the N -methyl group are in a cis relationship . A trans -amide has been reported to be thermodynamically favored over a cis -amide …”

mentioning

confidence: 99%

“…13−15 The X-ray structure of 1 bound to the ligand binding domain (LBD) of the PPARδ receptor revealed that the carbonyl oxygen and the N-methyl group are in a cis relationship. 13 A trans-amide has been reported to be thermodynamically favored over a cis-amide. 16 cis-Amides are uncommon even in the peptide literature, especially for amino acids other than proline.…”

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confidence: 99%

“…One of the nitrogen atoms in the imidazole ring of 13 forms a water-mediated interaction with Leu304 as was observed for the cis-amide in the X-ray structure for 1. 13 The binding interactions with Val312 and Ile328 have been postulated to impart selectivity for a known PPARδ selective modulator, GW0742. 22 Overlay of the crystal structures of 13 with GW0742 (PDB ID: 3TKM) reveals a significant downward movement of the Ile328 residue in the structure for 13, even though the Val312 conformation is conserved in both structures.…”

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confidence: 99%

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Selective PPARδ Modulators Improve Mitochondrial Function: Potential Treatment for Duchenne Muscular Dystrophy (DMD)

Lagu

Kluge

Tozzo

et al. 2018

ACS Med. Chem. Lett.

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The X-ray structure of the previously reported PPARδ modulator bound to the ligand binding domain (LBD) revealed that the amide moiety in exists in the thermodynamically disfavored -amide orientation. Isosteric replacement of the-amide with five-membered heterocycles led to the identification of imidazole (MA-0204), a potent, selective PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested in mice and in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); altered the expression of PPARδ target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients.

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PPARα and δ Ligand Design: Honing the Traditional Empirical Method with a More Holistic Overview

Chua

Bruning

2021

Nuclear Receptors

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Novel highly selective peroxisome proliferator-activated receptor δ (PPARδ) modulators with pharmacokinetic properties suitable for once-daily oral dosing

Cited by 10 publications

References 8 publications

An aPPARent Functional Consequence in Skeletal Muscle Physiology via Peroxisome Proliferator-Activated Receptors

An aPPARent Functional Consequence in Skeletal Muscle Physiology via Peroxisome Proliferator-Activated Receptors

Selective PPARδ Modulators Improve Mitochondrial Function: Potential Treatment for Duchenne Muscular Dystrophy (DMD)

PPARα and δ Ligand Design: Honing the Traditional Empirical Method with a More Holistic Overview

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